title: Association between common variation at the FTO locus and changes in body mass index from infancy to late childhood: the complex nature of genetic association through growth and development.
abstract: An age-dependent association between variation at the FTO locus and BMI in children has been suggested. We meta-analyzed associations between the FTO locus (rs9939609) and BMI in samples, aged from early infancy to 13 years, from 8 cohorts of European ancestry. We found a positive association between additional minor (A) alleles and BMI from 5.5 years onwards, but an inverse association below age 2.5 years. Modelling median BMI curves for each genotype using the LMS method, we found that carriers of minor alleles showed lower BMI in infancy, earlier adiposity rebound (AR), and higher BMI later in childhood. Differences by allele were consistent with two independent processes: earlier AR equivalent to accelerating developmental age by 2.37% (95% CI 1.87, 2.87, p = 10(-20)) per A allele and a positive age by genotype interaction such that BMI increased faster with age (p = 10(-23)). We also fitted a linear mixed effects model to relate genotype to the BMI curve inflection points adiposity peak (AP) in infancy and AR. Carriage of two minor alleles at rs9939609 was associated with lower BMI at AP (-0.40% (95% CI: -0.74, -0.06), p = 0.02), higher BMI at AR (0.93% (95% CI: 0.22, 1.64), p = 0.01), and earlier AR (-4.72% (-5.81, -3.63), p = 10(-17)), supporting cross-sectional results. Overall, we confirm the expected association between variation at rs9939609 and BMI in childhood, but only after an inverse association between the same variant and BMI in infancy. Patterns are consistent with a shift on the developmental scale, which is reflected in association with the timing of AR rather than just a global increase in BMI. Results provide important information about longitudinal gene effects and about the role of FTO in adiposity. The associated shifts in developmental timing have clinical importance with respect to known relationships between AR and both later-life BMI and metabolic disease risk.
authors.affiliation: Department of Epidemiology and Biostatistics, Imperial College, London, United Kingdom.
authors.forename: Ulla
authors.initials: U
authors.lastname: Sovio
authors.forename: Dennis O
authors.initials: DO
authors.lastname: Mook-Kanamori
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Warrington
authors.forename: Robert
authors.initials: R
authors.lastname: Lawrence
authors.forename: Laurent
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authors.lastname: Briollais
authors.forename: Colin N A
authors.initials: CN
authors.lastname: Palmer
authors.forename: Joanne
authors.initials: J
authors.lastname: Cecil
authors.forename: Johanna K
authors.initials: JK
authors.lastname: Sandling
authors.forename: Ann-Christine
authors.initials: AC
authors.lastname: Syvänen
authors.forename: Marika
authors.initials: M
authors.lastname: Kaakinen
authors.forename: Lawrie J
authors.initials: LJ
authors.lastname: Beilin
authors.forename: Iona Y
authors.initials: IY
authors.lastname: Millwood
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Bennett
authors.forename: Jaana
authors.initials: J
authors.lastname: Laitinen
authors.forename: Anneli
authors.initials: A
authors.lastname: Pouta
authors.forename: John
authors.initials: J
authors.lastname: Molitor
authors.forename: George
authors.initials: G
authors.lastname: Davey Smith
authors.forename: Yoav
authors.initials: Y
authors.lastname: Ben-Shlomo
authors.forename: Vincent W V
authors.initials: VW
authors.lastname: Jaddoe
authors.forename: Lyle J
authors.initials: LJ
authors.lastname: Palmer
authors.forename: Craig E
authors.initials: CE
authors.lastname: Pennell
authors.forename: Tim J
authors.initials: TJ
authors.lastname: Cole
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
authors.forename: Marjo-Riitta
authors.initials: MR
authors.lastname: Järvelin
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Timpson
mesh_terms: D050154:Adiposity / Q000235:genetics; D000293:Adolescent; D000483:Alleles; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D001827:Body Height / Q000235:genetics; D015992:Body Mass Index; D001835:Body Weight / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D003430:Cross-Sectional Studies; D005260:Female; D056726:Genetic Association Studies; D056426:Genetic Loci / Q000235:genetics*; D014644:Genetic Variation; D005838:Genotype; D048788:Growth and Development / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008137:Longitudinal Studies; D008297:Male; D015201:Meta-Analysis as Topic; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011506:Proteins / Q000235:genetics*
chemical_list: D011506:Proteins; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C526492:FTO protein, human